Two cannabinoid receptors are known: one is expressed predominately in the central nervous system (CB1), whereas the other is located in the periphery and is primarily restricted to cells and tissues derived from the immune system (CB2). (Abood and Martin Int. Rev. of Neurobio. 39, 197–221, (1996).
While agonists at the CB1 receptor, and mixed agonists, are highly effective in anti-nociception models in animals, it has not proved possible to separate the desired analgesic actions from the undesired CNS side-effects to any great degree. These undesired CNS side-effects are known to be mediated by the CB1 receptor.
A number of reports indicate an important role for CB2 in pathophysiology. In particular, Munro et. al. [Nature 365 61–65 (1993)] have found that the expression of the CB2 receptor is induced under conditions of immune cell activation. Hanus et. al [PNAS 96, 14228–14233 (1999)] have recently provided evidence that a CB2 agonist elicits anti-inflammatory and peripheral analgesic activity. Moreover, Mazzari et. al. [Soc. Neurosci. Abstr. 23 652 (1995)] have shown that CB2 activation inhibits mechanical hyperalgesia associated with nerve injury. These results indicate that the CB2 receptor is an interesting target for the discovery of novel analgesics which would be expected to be devoid of CB1 mediated side-effects associated with conventional cannabinoid agonists, e.g., tetrahydrocannabinol (THC). Moreover, as the CB2 receptors are limited to the periphery, selective CB2 agonists may be expected to reduce pain without the psychoactive side effects and the commonly perceived abuse potential of centrally acting cannabimimetic (CB1) or opiate drugs.
Analgesics that have been identified and are existing in the prior art have many disadvantages among which are poor pharmacokinetics and loss of analgesic activity when administered by systemic routes.